The objectives of this project are to (1) to provide experimental data for the modeling of Hg concentration in the brain of newborn animals (2); determine the dose-response for the probable neurotoxic effects in the newborn induced by maternal exposure to mercury vapor; and (3) to develop a pharmacokinetic simulation model for Hg distribution in the pregnant rat and to expand this model to humans. Toxicokinetic studies were conducted by exposing pregnant rats to either 1, 2, 4, or 8 mg/m3 Hg vapor. Tissues were collected from pregnant rats, fetuses and neonates and analyzed for total Hg content. A computer model is being developed using these toxicokinetic data. Because maternal toxicity was observed at 8 mg/m3, an exposure concentration of 4 mg/m3 was used in studies examining the potential developmental neurotoxicity of Hgo in the developing rat. Pregnant rats were exposed to 4 mg/m3 Hgo vapor from GD6 to GD15. Offspring were assessed from PND 21 to PND90 for a range of neurochemical, neuroanatomical and neurobehavioral endpoints. Renal metallothionein (MT) and glutathione (GSH) -related gene expression were measured after Hg vapor exposure (4 mg/m3) in non-pregnant, pregnant and neonatal rats exposed in utero. Hg vapor exposure produced a time-dependent increase in renal MT protein in non-pregnant and pregnant rats, but not in neonatal rats. Pregnant rats showed maximum increases in renal MT levels on GD15 (3-fold) and levels remained increased until the day after pups? birth (postnatal day 1). After that, renal MT levels began to decrease, but were still higher than controls. A similar pattern of sustained increases in renal MT occurred in Hg treated non-pregnant rats. Microarray analysis showed that the expression of the GST-pi gene was markedly increased, as was GST enzyme activity, in the kidneys of pregnant and non-pregnant rats. Thus, exposure to Hg vapor activates the MT and GST-pi genes and increases GST activity in pregnant and non-pregnant rats. Activation of renal MT and GST genes could be part of a defense response directed at decreasing renal toxicity of Hg, and may help divert the metal away from the fetus.